The mechanisms that lead to painful or insensate symptoms in diabetic neuropathy (DN) are poorly understood. Many variables likely play a role in the development of these diverse symptoms, including reduced neurotrophic supply, abnormal insulin support, and oxidative stress. These symptoms may also underlie peripheral axon damage amongst select sensory neuronal subpopulations. Our long-term goal is to understand the etiology of painful and/or insensate complications of DN in relation to insulin support, oxidative stress, and peripheral axon degeneration. The central hypothesis of this proposal is that unique genetic differences underlie the differential progression and severity of diabetic neuropathy. Exploring these genetic differences will help identify mechanisms involved in the pathogenesis of diabetic neuropathy. Aim 1 will characterize the progression of painful and insensate neuropathy in type 1 (STZ- A/J vs. STZ-C57Bl/6) and type 2 (ob/ob vs. db/db) mouse models of diabetes and test whether neurotrophins can alleviate the diabetes-induced abnormalities in mechanical sensitivity. Aim 2 will test whether insulin support plays a critical role in the progression of painful or insensate neuropathy amongst these variant mouse models of diabetes. Aim 3 will examine the role of oxidative stress in the development of painful or insensate neuropathy in these diabetic mice. Aim 4 will determine whether differential damage to epidermal axons is important factor in developing painful or insensate diabetic neuropathy. Collectively, these studies will identify three possible mechanisms responsible for the variable progression of symptoms experienced within human patients and identify new therapeutic targets aimed at the severity of symptoms amongst diabetic patients. PUBLIC HEALTH RELEVANCE: This proposal will elucidate mechanisms related to the development of painful versus nonpainful symptoms in mouse models of diabetic neuropathy. The role of neurotrophins, insulin support, oxidative stress, and axonal degeneration will be investigated to identify mechanisms that lead to the neural complications associated with diabetes.